1Cox, Lehninger Principles in Biochemistry, chapter 2, figure 23bElectron micrograph (false coloring) of budding HIV particlesHIV envelope structure and protease activityCox, Lehninger Principles in Biochemistry, chapter 26, figure 31HIV cell fusion and genome replication and integrationLife cycle of a virus part I2Life cycle of a virus part IIVoet&Voet, Biochemistry, chapter 15The assembly, budding, and maturation of HIV (Figure 15-33 )3Attachment and entry into cells by HIVPaul R. Clapham and Áine McKnight Cell surface receptors, virus entry and tropism of primate lentiviruses J Gen Virol 2002 83: 1809-1829Sequential interactions between the HIV virion spike glycoprotein and CD4 followed by a coreceptor triggers fusion of the virion and cellular membranes and subsequent virus entrySequential interactions between the HIV virion spike glycoprotein and CD4 followed by a coreceptor triggers fusion of the virion and cellular membranes and subsequent virus entryAttachment and entry into cells by HIVPaul R. Clapham and Áine McKnight Cell surface receptors, virus entry and tropism of primate lentiviruses J Gen Virol 2002 83: 1809-1829Complexing of the leucine zipper domain (red) and a-helix (blue) repositions the gp41 TM region and fusion domains close together allowing a fusion pore to formHIV virion binds CD4.Conformation changes in the core of gp120 an co-receptor-bindingCo-receptor triggers changes in gp41 releasing the fusion domain4The role of gp41 in the formation of the fusion pore.Paul R. Clapham and Áine McKnight Cell surface receptors, virus entry and tropism of primate lentiviruses J Gen Virol 2002 83: 1809-1829(A) Interaction of gp120 with CD4 and a coreceptor exposes the fusion domain (blue triangle). (B) Complexing of the leucine zipper-like region(red) and a-helix (blue) positions the virion and cell membranes close together. Several gp41 molecules are probably needed to form a fusion pore. (C) The outer membranes fuse together at the hemifusion stage. (D) The hemifusion stage is usually short-lived and fusion of the internal membranes follows rapidly. The core inside the virus particle is now exposed to the cell cytoplasm and further uncoating events are needed to allow disassociation from virion membrane and transport of the preintegration complex through the cytoplasm.virioncytoplasmvirioncytoplasmInhibitors of membrane fusion mechanismFig. X-ray structure of fusogenic gp41; three helical N-peptides (light) in a coiled-coil con-formation surrounded by three helical C-peptides (dark) (from Eckert and Kim, 2001)5Protease InhibitorsFigure 15-38b X-Ray structure of HIV-1 protease. (b) In complex with its inhibitor.Figure 15-34a HIV-1 polyproteins. (a) The organization of the HIV-1 gag and gag–pol polyproteins.Voet&Voet, Biochemistry, chapter 156Figure 15-36aX-Ray structure of pepsin. (a) Ribbon diagram.Figure 15-38aX-Ray structure of HIV-1 protease. (a) Uncomplexed.Voet&Voet, Biochemistry, chapter 15(from Levy, 1993)Ribbon diagram of HIV protease dimer without (A) with inhibitor (B)7Asp25Asp25'COOCOOHOHH-HIV protease -Asp-Thr-Gly-Ala-pepsin -Asp-Thr-Gly-Thr/Ser-Catalytic diad of HIV proteaseFigure 15-37Catalytic mechanism of aspartic proteases.Voet&Voet, Biochemistry, chapter 158NCCOHR1NCR1'COHPeptidebondNCCOR1CHCR1'COHPeptide substratePeptide mimeticHHHydroxy-ethyleneHHHHHFigure 15-40Comparison of a normal peptide bond to several groups (red) that are similar to the tetrahedral intermediate of aspartic proteases.Figure 15-41Some HIV-1 protease inhibitors that are in clinical use.Voet&Voet, Biochemistry, chapter
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